The accurate measurement of pulmonary ventilation (V), perfusion (Q), and V/Q distribution is of great importance in medicine. V/Q relationships are used to diagnose and treat pulmonary disorders, including emphysema, asthma and pulmonary embolus. Established methods for anatomic study of gas exchange in the human lung include conventional planar ventilation and perfusion nuclear scanning (V/Q scans) and single photon emission-computed tomography (SPECT). However, existing techniques have well-documented, clinically significant limitations. Moreover they are unfortunately limited in spatial resolution, and they involve the mandatory exposure of both the patient and the practitioner to radioactive agents. They also require prolonged breathing from an increased resistance closed system through a tight-fitting facemask, an effort that some patients with advanced emphysema are unable to tolerate.
Normally, pulmonary artery blood flows through capillaries that are immediately proximate to alveoli. For gas exchange to occur efficiently, alveolar ventilation and pulmonary blood flow are proportionally matched. When V/Q mismatch occurs, the terms “shunting” or “dead space” are used to describe the abnormalities in V or Q, respectively. Shunting occurs when unventilated or collapsed alveoli cannot participate in gas exchange (i.e., unloading carbon dioxide and absorbing oxygen), so that there is diversion in the blood flow. Likewise, without blood flow to an alveolus, wasted ventilation or dead space occurs. While small amounts of shunting (e.g., in the bronchial vessels) and dead space (e.g., in the nasopharyx) are normal, a significant number of pathological pulmonary conditions are characterized by V/Q mismatches.
Pulmonary functional imaging methods include qualitative tests that provide valuable clinical information, but each currently available test has a limitation. The radionuclide V/Q scan has inherently poor spatial relations, lacks the ability to image cross-sectional views, and deposits radiolabeled aerosols in the central airways of the patient, causing errors. SPECT has the highest resolution of all of the known methods, but accurate detection of pulmonary disorders still demands even higher resolution than is currently provided. Global pulmonary function may be determined by the multiple inert gas elimination technique (MIGET), which provides a quantitative measurement of pulmonary V/Q ratios based upon a mathematical subdivision of the lung into fifty hypothetical segments. It is the gold-standard physiological test of lung V/Q relationships, but even MIGET has characteristic and problematic limitations, which have prevented its widespread clinical application. For instance, large blood sample volumes are necessary for the analysis.
Ventilation scanning using non-radioactive xenon gas and ultrafast computed tomography has been described (Murphy et al., Chest 96:799-804 (1989), but requires exposure to radiation in the form of x-rays. Low signal intensity and the effects of respiratory motion have likewise limited conventional proton MR imaging of human airways and the pulmonary parenchyma (Bergin et al., Radiology 179:777-781 (1991); Bergin et al., Radiology 180: 845-848 (1991); Bergin et al., J. Thorac. Imag. 8:12-17 (1993); Alsop et al., Magn. Reson. Med. 33: 678-682 (1995)).
The use of hyperpolarized noble gases, such as 3He, has been demonstrated to be useful in the imaging of gas distribution (ventilation) in the human lung (Middleton et al., Mag. Res. Med. 33:271-275 (1995); MacFall et al., Rad 200:553-558 (1996); Kauczor et al., Rad 201:564-568 (1996); Kauczor et al, J. Mag. Res. Imag. 7:538-543 (1997); Roberts et al., Mag. Res. Med. 44(3):379-382 (2000); Black et al., Rad 199(3):867-870 (1996); de Lange et al., Rad 210(3):851-857 (1999); Altes et al., J. Mag. Res. Imag. 13(3):378-384 (2001); Salerno et al., Mag. Res. Med. 46:667-677 (2001); Gierada et al., NMR Biomed. 13(4):176-181 (2000)). When hyperpolarized helium-3 (HP-3He) has been used in the lung, regional oxygen partial pressure (O2) has been calculated from the intensity of the HP-3He magnetic resonance (MR) images, but it has not been previously applied to V/Q measurements.
Thus, the ideal radiologic method for assessing gas exchange would quantify the comparison of V/Q in small volumetric zones of the lung. It would be safe, non-invasive, rapid, easily applied, reproducible and tolerable to patients with advanced lung disease. To date, no available technique met all of these requirements.
Arterial blood perfusion imaging can be obtained by noninvasive magnetic labeling of blood using the arterial spin-tagging (AST) technique (see, e.g., U.S. Pat. No. 5,402,785, Leigh and Alsop). This method is based upon the steady-state magnetic labeling, or “spin-tagging” of arterial water protons (Detre et al., NMR Biomed. 7:75-82 (1994); Roberts et al., Proc. Natl. Acad. Sci. USA 91: 33-37 (1994); Roberts et al., Proc. Fifth Scientific Meeting and Exhibition of ISMRM 3:1764 (1997); Roberts et al., Rad 212(3):890-895 (1999); Detre et al., Magn. Res. Med. 22:37-45 (1992); Roberts et al., J. Magn. Reson. Imag. 14(2):175-180 (2001)).
The combined application of these two non-invasive functional MR imaging techniques would provide images of the patterns of air flow in the lungs of human or animal subjects, and aid in V/Q mapping of the lung. Prior to the present invention, however, although qualitative methods are known, no noninvasive quantitative method for imaging lung ventilation has been used or developed. Moreover V/Q by magnetic resonance imaging (MRI) would offer a new ability to uniquely describe normal lungs, to diagnose pulmonary disease, to follow the course of pulmonary diseases, and to assess therapeutic response in terms of localized V/Q (regional VIQ). Accordingly, a need has remained in the art until the present invention for a quantitative method of rapidly providing accurate V/Q images at very high resolution, and an invention meeting these needs would provide valuable insight into the pathogenesis and pathophysiology of pulmonary V/Q abnormalities and of the normal lung.